![]() Since hypermethylation of CpG-cytosines in promoter regions is a frequent mechanism for transcriptional inactivation,, , we explored these possible variations in AE2/SLC4A2 promoter regions. ![]() 34 However, the genetic and/or epigenetic factors responsible for the decreased AE2 mRNA expression in PBC 17 remain to be fully elucidated. 33 More recent findings provided evidence for upregulation of microRNA 506 in PBC bile-duct cells being involved in the decreased liver expression of AE2 protein through blocking the translation (but not the transcription) of AE2 messages. 32 Also, a synonymous variation in exon 6 (rs2303932) was related with the progression of the disease in a French population. 31 But in Caucasian patients, no association between variations in AE2/SLC4A2 and PBC susceptibility has been reported, though single-nucleotide polymorphism analyses across this gene have found 2 variants influencing AMA status. ,, Ĭonventional genotyping of selected AE2/SLC4A2 tag single-nucleotide polymorphisms (rs2069443, rs2303933, rs2303937, and rs2303941) in Japanese patients with PBC revealed associations with disease susceptibility and/or anti-centromere antibody production. 17 The notion that diminished AE2 might be involved in PBC pathogenesis received definite support from our findings in Ae2-knockout mice, which exhibit characteristic features resembling PBC. 18 Also, we reported that AE2 mRNA levels are decreased in liver biopsies and peripheral blood mononuclear cells (PBMCs) from patients with PBC. ,, Previously, we reported that bile-duct cells isolated from PBC patients exhibit defective cAMP-stimulated AE activity, 20 and that PBC livers have diminished AE2 expression at the luminal membrane of the biliary epithelium. ![]() 22 AE2/SLC4A2 gene-silencing experiments indicated that AE2 is the main carrier for this activity in cholangiocytes. ,, , Bicarbonate secretion occurs at the apical membrane of bile-duct cells via electroneutral Na +-independent Cl –/HCO 3 – anion exchange (AE), which can be stimulated by cAMP, the second messenger for secretin signal transduction. In humans, secretin-stimulated biliary bicarbonate secretion is crucial for adequate bile modifications along the biliary tract. ,, ,, Indeed, positron-emission-tomography studies showed that untreated patients with PBC failed to increase biliary bicarbonate in response to secretin, while treatment with UDCA for a few months could reverse this defect. ,, ,, Since the hydrophilic bile acid UDCA is known to induce bicarbonate-rich choleresis, we have been postulating that primary or secondary abnormalities in the mechanisms responsible for biliary bicarbonate secretion might have a pathogenic role in PBC. Notwithstanding these features of autoimmunity in PBC, the therapeutic regimes with potent immunosuppressants have shown little efficacy, which is particularly intriguing if compared with the substantial benefit obtained in most patients with early PBC undergoing therapy with ursodeoxycholic acid (UDCA). Certainly, the disease is strongly associated with autoimmune phenomena, such as the presence of autoreactive T cells in portal infiltrates and high-titer serum antimitochondrial autoantibodies (AMA) that recognize antigens at the inner mitochondrial membrane. 6 Genome-wide-association studies (GWAS), ,, and dense fine-mapping association studies 11 have related susceptibility to PBC with genetic variations in genes pertinent to immunity like HLA type II, IL12A, IL12RB2, IL21 and IL21R genes among others. The disease is regarded as a complex multifactorial disease that may be triggered by environmental factors in individuals with genetic predisposition. ,, , Thus far, the etiopathogenesis of PBC remains elusive. Primary biliary cholangitis (PBC), formerly named primary biliary cirrhosis, 1 is a chronic cholestatic liver disease mostly affecting middle-aged women, in which portal mononuclear infiltrates result in progressive damage and destruction of interlobular bile ducts.
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